US8404841B2 - Process for the preparation of statins and their pharmaceutically acceptable salts thereof - Google Patents
Process for the preparation of statins and their pharmaceutically acceptable salts thereof Download PDFInfo
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- US8404841B2 US8404841B2 US12/531,386 US53138607A US8404841B2 US 8404841 B2 US8404841 B2 US 8404841B2 US 53138607 A US53138607 A US 53138607A US 8404841 B2 US8404841 B2 US 8404841B2
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- VQYHOAWFBHVYCF-OHQDXVBBSA-M CC(C)(C)[NH].CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)O)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(CS(=O)(=O)C2=NC3=C(C=CC=C3)N2C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CCCCNC(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1.CCCCNC(=O)C[C@H]1C[C@@H](/C=C/C2=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C2C2=CC=C(F)C=C2)OC(C)(C)O1.CCCCNC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1.[Ca+2] Chemical compound CC(C)(C)[NH].CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)O)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(CS(=O)(=O)C2=NC3=C(C=CC=C3)N2C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CCCCNC(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1.CCCCNC(=O)C[C@H]1C[C@@H](/C=C/C2=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C2C2=CC=C(F)C=C2)OC(C)(C)O1.CCCCNC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1.[Ca+2] VQYHOAWFBHVYCF-OHQDXVBBSA-M 0.000 description 1
- RFPDKVGYOUBFEW-JHJMCBSOSA-M CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.CN1C(S(=O)(=O)CC2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)=NC2=C1C=CC=C2.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.[Ca+2] Chemical compound CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.CN1C(S(=O)(=O)CC2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)=NC2=C1C=CC=C2.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.[Ca+2] RFPDKVGYOUBFEW-JHJMCBSOSA-M 0.000 description 1
- JXECIVRRSLIQLM-PNCBYXDNSA-M CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.FC1=CC=C(C2=C(C[P+](C3=CC=CC=C3)(C3=CC=CC=C3)C3=CC=CC=C3)C(C3CC3)=NC3=CC=CC=C32)C=C1.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.[Br-].[Ca+2] Chemical compound CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.FC1=CC=C(C2=C(C[P+](C3=CC=CC=C3)(C3=CC=CC=C3)C3=CC=CC=C3)C(C3CC3)=NC3=CC=CC=C32)C=C1.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.[Br-].[Ca+2] JXECIVRRSLIQLM-PNCBYXDNSA-M 0.000 description 1
- DXCGMPDTNOQICN-JHJMCBSOSA-M CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=P(CC1=C(C2=CC=C(F)C=C2)C2=CC=CC=C2N=C1C1CC1)(C1=CC=CC=C1)C1=CC=CC=C1.[Ca+2] Chemical compound CC(C)(C)[NH].CC(C)N(C(=O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](/C=C/C2=C(C3=CC=C(F)C=C3)C3=C(C=CC=C3)N=C2C2CC2)OC(C)(C)O1)C(C)C.CC(C)N(C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1)C(C)C.O=C(O)C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=C([O-])C[C@H](O)C[C@H](O)/C=C/C1=C(C2=CC=C(F)C=C2)C2=C(C=CC=C2)N=C1C1CC1.O=P(CC1=C(C2=CC=C(F)C=C2)C2=CC=CC=C2N=C1C1CC1)(C1=CC=CC=C1)C1=CC=CC=C1.[Ca+2] DXCGMPDTNOQICN-JHJMCBSOSA-M 0.000 description 1
- PPDLIPFMPCCORU-DQHZHOIBSA-N CC(C)/C1=C(\C2=CC=C(F)C=C2)C2=CC=CC=C2N1C(C)C.CC(C)C1=C(C(C)C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(C2=CC=C(F)C=C2)C2=CC=CC=C2N=C1C1CC1.CC[C@H](C)C(=O)OC1C[C@H](O)C=C2C=C[C@@H](C)[C@H](C(C)C)C21.COCC1=C(C2=CC=C(F)C=C2)C(C(C)C)=C(C(C)C)N=C1C(C)C Chemical compound CC(C)/C1=C(\C2=CC=C(F)C=C2)C2=CC=CC=C2N1C(C)C.CC(C)C1=C(C(C)C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.CC(C)C1=C(C2=CC=C(F)C=C2)C2=CC=CC=C2N=C1C1CC1.CC[C@H](C)C(=O)OC1C[C@H](O)C=C2C=C[C@@H](C)[C@H](C(C)C)C21.COCC1=C(C2=CC=C(F)C=C2)C(C(C)C)=C(C(C)C)N=C1C(C)C PPDLIPFMPCCORU-DQHZHOIBSA-N 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-M CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.[Ca+2] Chemical compound CC(C)C1=C(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1.[Ca+2] BPRHUIZQVSMCRT-VEUZHWNKSA-M 0.000 description 1
- LQZCMWGZSBZXSB-UHFFFAOYSA-N CC(C)C1=C(C(C)C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1 Chemical compound CC(C)C1=C(C(C)C)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1 LQZCMWGZSBZXSB-UHFFFAOYSA-N 0.000 description 1
- CVRDGWDBQZPJJI-UHFFFAOYSA-N CC(C)C1=C(CP(=O)(C2=CC=CC=C2)C2=CC=CC=C2)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1 Chemical compound CC(C)C1=C(CP(=O)(C2=CC=CC=C2)C2=CC=CC=C2)C(C2=CC=C(F)C=C2)=NC(N(C)S(C)(=O)=O)=N1 CVRDGWDBQZPJJI-UHFFFAOYSA-N 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC(O)=O)O)O Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1/C=C/[C@H](C[C@H](CC(O)=O)O)O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- YNUMWQDBPHQVSQ-UHFFFAOYSA-N CC(c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1C1)[O]=S1(c1nc(cccc2)c2[n]1C)=O Chemical compound CC(c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1C1)[O]=S1(c1nc(cccc2)c2[n]1C)=O YNUMWQDBPHQVSQ-UHFFFAOYSA-N 0.000 description 1
- XGQNMVJAOPOSDR-KRPSDTOLSA-N CCC(C)(C)C(=O)OC1C[C@@H](C)C=C2C=C[C@@H](C)[C@H](C(C)C)C21.CC[C@H](C)C(=O)OC1C[C@@H](C)C=C2C=C[C@@H](C)[C@H](C(C)C)C21 Chemical compound CCC(C)(C)C(=O)OC1C[C@@H](C)C=C2C=C[C@@H](C)[C@H](C(C)C)C21.CC[C@H](C)C(=O)OC1C[C@@H](C)C=C2C=C[C@@H](C)[C@H](C(C)C)C21 XGQNMVJAOPOSDR-KRPSDTOLSA-N 0.000 description 1
- ZAJNMXDBJKCCAT-YFKPBYRVSA-N CCOC(=O)C[C@H](O)CCl Chemical compound CCOC(=O)C[C@H](O)CCl ZAJNMXDBJKCCAT-YFKPBYRVSA-N 0.000 description 1
- POBCMLCYKPMAMU-ZETCQYMHSA-N CN(C)C(=O)CC(=O)C[C@H](O)CCl Chemical compound CN(C)C(=O)CC(=O)C[C@H](O)CCl POBCMLCYKPMAMU-ZETCQYMHSA-N 0.000 description 1
- CJFMQAJFXOZLCA-RQJHMYQMSA-N CN(C)C(=O)C[C@@H](C[C@@H](C=O)OP)OPP Chemical compound CN(C)C(=O)C[C@@H](C[C@@H](C=O)OP)OPP CJFMQAJFXOZLCA-RQJHMYQMSA-N 0.000 description 1
- SFSGWNZMQBINAU-RQJHMYQMSA-N CN(C)C(=O)C[C@@H](C[C@@H](CCl)OP)OPP Chemical compound CN(C)C(=O)C[C@@H](C[C@@H](CCl)OP)OPP SFSGWNZMQBINAU-RQJHMYQMSA-N 0.000 description 1
- BRJOKAQXBMMVKN-RQJHMYQMSA-N CN(C)C(=O)C[C@@H](C[C@@H](CO)OP)OPP Chemical compound CN(C)C(=O)C[C@@H](C[C@@H](CO)OP)OPP BRJOKAQXBMMVKN-RQJHMYQMSA-N 0.000 description 1
- QHLTVXWXXAKMAE-RQJHMYQMSA-N CN(C)C(=O)C[C@H](O)C[C@H](O)CCl Chemical compound CN(C)C(=O)C[C@H](O)C[C@H](O)CCl QHLTVXWXXAKMAE-RQJHMYQMSA-N 0.000 description 1
- DDJOPKXVBXWCGW-GDVGLLTNSA-N O=C1CC(CO)C[C@H](O)C1 Chemical compound O=C1CC(CO)C[C@H](O)C1 DDJOPKXVBXWCGW-GDVGLLTNSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to a novel process for the preparation of statins and their pharmaceutically acceptable salts thereof represented by the general formula-1,
- R is a hydrophobic anchor or a residue of HMG CoA reductase inhibitor selected from any one of the compound of formula-a to formula-g,
- M is H, Na + , K + , Mg +2 , Ca +2
- the compounds of the present invention inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
- the present invention relates to a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates,
- M is H, Na + , K + , Mg +2 , Ca +2 and R is as defined above.
- the first aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediate compounds by employing Julia-modified olefination.
- the second aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediate compounds by employing Wittig-horner reaction.
- the third aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediate compounds by employing Wittig reaction.
- the fourth aspect of the present invention is to provide novel amide compounds of general formula-3 and process for their preparation.
- the fifth aspect of the present invention is to provide novel sulfone, sulfide and sulfoxide compounds and process for their preparation.
- Rosuvastatin and its pharmaceutically acceptable salts were first disclosed in U.S. Pat. No. 5,260,440. It also discloses process for their preparation.
- the United States patent application number US 2005/0124639 disclosed another alternate process for the preparation of rosuvastatin and its intermediates through wittig reagents.
- the disclosed process involves the condensation of wittig reagent like triphenyl[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl]phosphonium bromide or other reagent with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl ⁇ acetate in a suitable solvent in presence of a base to provide tertiary butyl ester compound of rosuvastatin which is further converted into free acid then to calcium salt by contacting with a calcium source.
- wittig reagent like triphenyl[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsul
- statins are very important inhibitors of the HMG CoA reductase; hence there is a need to develop a novel cost effective process for their preparation.
- the present invention provides a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds through novel intermediates which are more effective and easy to scale up in commercial batches in a convenient and cost effective manner.
- statins and their pharmaceutically acceptable salts which are useful as anti-cholesterol agents as described hereinafter.
- the first aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates by employing Julia-modified olefination,
- the second aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates, which comprises of the following steps:
- the third aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates by employing wittig reaction, which comprises of the following steps:
- the fourth aspect of the present invention is to provide a novel amide intermediate compounds of general formula-3, which are useful for the preparation of HMG-CoA reductase inhibitors,
- the fifth aspect of the present invention is to provide an alternate process for the preparation of novel amide compounds of formula-3 useful as intermediates for the preparation of HMG-CoA reductase inhibitors, which comprises of the following steps:
- the sixth aspect of the present invention is to provide a novel sulfone, sulfide and sulfoxide compounds and process for their preparation, which comprises of the following steps:
- the process of the present invention may employed to prepare rosuvastatin, pravastatin, cerivastatin, fluvastatin, nisvastatin (pitavastatin), simvastatin, lovastatin and other dihydroxy acid or lactone HMG CoA reductase inhibitors.
- statins HMG-CoA reductase inhibitors
- their pharmaceutically acceptable salts which are useful as anti-cholesterol agents as described hereinafter.
- lower alkyl refers to a straight or branched or cyclic C 1 to C 6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and isohexyl and the like.
- the lower alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, hydroxy and cyano.
- Halogen means fluorine chlorine, bromine and iodine.
- alkyl refers to straight or branched or cyclic C 7 -C 12 alkyl
- aryl refers to C 6 -C 12 aromatic group include phenyl, tolyl, xylyl, biphenyl, naphthyl and the like.
- the aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy.
- aralkyl refers to C 1 -C 6 lower alkyl substituted by C 6 -C 12 aromatic aryl group defined above.
- benzyl, phenylethyl, phenylpropyl and the like each of which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy and the like.
- salts refers to the salt in which the cation is an alkali metal ion, an alkaline earth metal ion, or an ammonium ion.
- alkali metals are lithium, sodium, potassium and cesium
- alkaline earth metals are beryllium, magnesium, and calcium. Sodium and calcium are preferred.
- hydrophobic anchor or residue of an HMG-CoA reductase inhibitor employed herein denotes a “portion” or a “half” of the statin molecule, which is linked to the “other half” or “portion” i.e. dihydroxy acid or amide side chain.
- statins refers to the HMG-CoA reductase inhibitors like rosuvastatin, pravastatin, cerivastatin, fluvastatin, nisvastatin (pitavastatin), simvastatin, lovastatin and other dihydroxy acid HMG CoA reductase inhibitors.
- the first aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates by employing Julia-Modified olefination,
- R is defined as above which is linked to sulphur atom with a methylene group (—CH 2 —) and R 1 is
- R 2 is alkyl, aryl, arylalkyl or cycloalkyl
- R 3 is H, alkyl, aryl, arylalkyl, CF 3 , halo or NO 2
- R 4 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
- X is O, N—H, N-alkyl or S
- alkenyl double bond in free acid compound of general formula-6 may be reduced by hydrogenation (H 2 /Pd/C) in a suitable solvent to provide saturated alkyl acid compound of general formula-7,
- M is H, Na + , K + , Mg +2 , Ca +2 .
- alkali metal hydroxide refers to sodium hydroxide, potassium hydroxide and the like
- alkali metal alkoxide refers to the sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide and the like;
- alkali metal carbonate refers to sodium carbonate, potassium carbonate, cesium carbonate and the like.
- amide bases refers to sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl) amide and the like.
- metal hydrides refers to sodium hydride and potassium hydride and the like.
- alkyl metals refers to butyl lithium and the like.
- alkaline earth metal salts refers to calcium acetate, calcium chloride, calcium bromide and magnesium chloride and the like.
- polar aprotic solvents refers to dimethylsulfoxide, dimethylacetamide, dimethyl formamide, tetrahydrofuran and the like;
- polar protic solvents refers to water and the like
- hydrocarbon solvents refers to toluene, xylene, cyclohexane, hexane, heptane and the like.
- ketone solvents refers to acetone, methyl isobutyl ketone and the like.
- esters solvents refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like.
- alcoholic solvents refers to the methanol, ethanol, isopropanol, 2-butanol, ethylene glycol and the like.
- chloro solvents refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like.
- protecting agent refers to the alcohol protecting groups such as silyl like trimethylsilyl, triethylsilyl, tertiarybutyl dimethyl silyl, triisopropylsilyl, tertiraybutyldipropyl silyl and the like; diol protecting agent such as 2,2-dialkoxy alkanes like 2,2-dimethoxy propane and the like.
- phase transfer catalyst refers to the tetra-n-butylammonium bromide or methyltrioctylammonium chloride and the like.
- the second aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of the general formula-1 through novel intermediate compounds,
- M is H, Na + , K + , Mg +2 , Ca +2 and R is as defined above which comprises of reacting the diphenyl phosphine oxide compound of general formula-8,
- R is defined as above which is linked to phosphorus atom with a methylene group (—CH 2 —) With an amide compound of general formula-3
- P 1 , P 2 , R′ & R′′ are defined as above in presence of a suitable base selected from alkali or alkaline earth metal alkoxide/hydroxide, alkali metal carbonates, amide bases, alkyl metals and metal hydrides preferably amide bases in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ketone solvents, ester solvents or mixtures thereof preferably polar aprotic solvents, followed by isolation using suitable hydrocarbon solvents to provide olefin compound of general formula-4,
- M is H, Na + , K + , Mg +2 , Ca +2 .
- the third aspect of the present invention is to provide a novel process for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1 through novel intermediates by employing wittig reaction,
- R is defined as above which is linked to phosphorus atom with a methylene group (—CH 2 —)
- amide compound of general formula-3
- P 1 , P 2 , R′ & R′′ are defined as above in presence of a suitable base selected from alkali or alkaline earth metal alkoxide/hydroxide, alkali metal carbonates, amide bases, alkyl metals and metal hydrides preferably alkali metal carbonates in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ketone solvents, ester solvents or mixtures thereof preferably polar aprotic solvents, followed by isolation using suitable hydrocarbon solvents to provide olefin compound of general formula-4,
- a suitable solvent selected from polar protic solvents, alcoholic solvents, nitrile solvents, ketone solvents or mixtures thereof preferably polar protic solvents to provide pharmaceutically acceptable salt of statin compounds of general formula-1.
- M is H, Na + , K + , Mg +2 , Ca + .
- the fourth aspect of the present invention is to provide novel amide compounds of general formula-3 which are useful as intermediate for the preparation of statins and their pharmaceutically acceptable salt compounds of general formula-1,
- the present invention also provides a process for the preparation of novel amide compounds of general formula-3 useful for the preparation of HMG-CoA reductase inhibitors, which comprises of the following steps:
- the present invention also provides an alternate process for the preparation of amide compounds of general formula-3 useful for the preparation of HMG-CoA reductase inhibitors, which comprises of the following steps:
- the sixth aspect of the present invention is to provide novel sulfone compounds of general formula-2, sulfoxide compounds of general formula-24, sulfide compounds of general formula-23 and process for their preparation.
- the present invention provides a process for the preparation of novel sulfone compound of general formula-2 and sulfoxide compound of general formula-24,
- R is defined as above which is linked to the sulphur atom with a methylene group (—CH 2 —) and R 1 is defined as above, which comprises of the following steps:
- a suitable polar protic solvent such as water
- a preferred process for the preparation of rosuvastatin calcium compound of formula-1a by employing Julia-modified olefination which comprises of the following steps:
- a suitable polar protic solvent such as water
- a preferred process for the preparation of rosuvastatin calcium compound of formula-1a, which comprises of the following steps:
- a suitable polar protic solvent such as water
- a preferred process for preparing rosuvastatin calcium compound of formula-1a by employing Wittig reaction, which comprises of the following steps:
- a suitable polar protic solvent such as water
- a preferred process for the preparation of rosuvastatin calcium compound of formula-1a by employing Wittig reaction, which comprises of the following steps:
- a suitable polar protic solvents such as water to provide rosuvastatin calcium compound of formula-1a
- the starting material sulfone compound of formula-2 for all statins can be prepared by the process described in our earlier Indian patent application number 805/CHE/2006 and co-pending International application number PCT/IN07/000,172.
- the starting material biphenyl phosphine oxide compound of formula-8 for all statins can be prepared as per the process disclosed in the U.S. Pat. No. 6,844,437.
- triphenyl phosphonium bromide salt compound of formula-9 for all statins can be prepared as per the process disclosed in the patent application number US 2005/124639.
- All the stereoisomers of the compounds prepared herein are contemplated, either in admixture or in pure or substantially pure form.
- the compounds can have asymmetric centers at any of the carbon atoms including any one or the substitutents. Consequently, compounds of formula-1 can exist in an enantiomeric or diastereomeric forms or in mixtures thereof.
- the processes for preparation can utilizes racemates, enantiomers or diasteriomers as starting materials. When diasteromeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
- the particle size distribution of rosuvastatin calcium determined by laser scattering particle size distribution analyzer model Malvern Mastersizer 2000 having an accessory Scirocco 2000 using dry method technique with following specification: feed rate is 50%; air pressure is 2.0 bar; particle refractive index is 1.450; absorption is 0.1 and dispersant refractive index is 1.0
- HPLC Analysis of rosuvastatin is carried out using a liquid chromatograph is equipped with variable wavelength UV-Detector or PDA-Detector having Symmetry, C18, 250 ⁇ 4.6 mm, 5 ⁇ m or equivalent, at a wavelength of 248 nm at ambient temperature, load is 20 ⁇ l, runtime is 70 minutes, the diluent is a mixture of water and acetonitrile in the ratio of 1:1 and the mobile phase used is a mixture of water:acetonitrile:methanol:triethylamine in the ratio of 450:250:350:1 v/v and adjusted the pH to 4.5 with glacial acetic acid.
- UV-Detector or PDA-Detector having Symmetry, C18, 250 ⁇ 4.6 mm, 5 ⁇ m or equivalent, at a wavelength of 248 nm at ambient temperature, load is 20 ⁇ l, runtime is 70 minutes, the diluent is a mixture of water and acetonitrile in the ratio of 1:1 and the mobile phase used
- a process for packing and storage of amorphous rosuvastatin calcium comprises of the following steps:
- the oxygen busters can be used inside the black colour polyethylene bag and a triple laminated bag.
- a process for packing and storage of amorphous pitavastatin calcium comprises of the following steps:
- the oxygen busters can be used inside the black colour polyethylene bag and a triple laminated bag.
- the bulk density and tapped density of rosuvastatin calcium were determined according to the method given in the US pharmacopeia.
- the present invention schematically represented as the following schemes the invention not limited to rosuvastatin, pravastatin, cerivastatin, fluvastatin, nisvastatin (pitavastatin), simvastatin and lovastatin.
- Potassium carbonate 35 grams is added to a solution of 25 grams of sulfone compound of formula-2a, 25 ml of dimethyl sulfoxide at 25 to 35° C. Added 11 grams of 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-diisopropylacetamide to the above reaction mixture. Stirred the reaction mixture for 13 hours at 60 to 65° C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70° C. Hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45° C. for 6 hours.
- the compound of formula-4a (10 grams) was dissolved in 100 ml of acetonitrile at 25-30° C. The reaction mixture was cooled to 23-28° C. Aqueous hydrochloric acid (0.30 ml in 28 ml of water) was added to the reaction mixture slowly at 23-28° C. Stirred the reaction mixture for 4 hours at 23-28° C. The reaction mixture was quenched with aqueous sodium bicarbonate solution at 23-28° C. Sodium chloride solution was added to the reaction mixture and stirred for 15 minutes. Organic and aqueous layers were separated. The solvent from organic layer was completely distilled off under reduced pressure at below 50° C. Cyclohexane (60 ml) was added to the above obtained residue. The reaction mixture was stirred for 60 minutes at 25-30° C. Filtered the solid obtained and washed with cyclohexane.
- IR spectrum 3380, 2967, 1601, 1547, 1509, 1437, 1334, 1382, 1228, 1153, 843, 775 cm ⁇ 1 .
- the dihydroxy compound of formula-4-x′′ (5 grams) was dissolved in 25 ml of ethylene glycol at 25-30° C.
- Aqueous sodium hydroxide solution (2.5 grams in 10 ml of water) was added to the above reaction mixture.
- the reaction mixture was heated to 90-95° C. Stirred the reaction mixture for 4 hours at 90-95° C. Cooled the reaction mixture to 25-30° C.
- Water (50 ml) was added to the reaction mixture at 25-30° C.
- the reaction mixture was quenched with aqueous hydrochloric acid.
- Ethylaceate (100 ml) was added to the reaction mixture.
- the organic and aqueous layers were separated.
- the ethyl acetate layer was cooled to 0-10° C.
- the dihydroxy compound of formula-4-x′′ (5 grams) was dissolved in 25 ml of isopropyl alcohol at 25-30° C.
- Aqueous sodium hydroxide solution (2.5 grams in 10 ml of water) was added to the above reaction mixture.
- the reaction mixture was heated to reflux. Stirred the reaction mixture for 4 hours at reflux. Cooled the reaction mixture to 25-30° C.
- Water (50 ml) was added to the reaction mixture at 25-30° C.
- the reaction mixture was quenched with aqueous hydrochloric acid.
- Ethylaceate (100 ml) was added to the reaction mixture.
- the organic and aqueous layers were separated. The ethyl acetate layer was cooled to 0-10° C.
- the tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2,-dimethyl-1,3-dioxan-4-yl)acetate (50 grams) was dissolved in 500 ml of acetonitrile. The reaction mixture was cooled to 25-30° C. Aqueous hydrochloric acid solution (7.5 ml of hydrochloric acid in 125 ml of water) was added to the above reaction mixture slowly at 25-30° C. for 2 hours. The reaction mixture was stirred for 2 hours at 25-30° C. The reaction mixture was quenched with aqueous sodium bicarbonate solution. The reaction mixture was stirred for 30 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined and dried over sodium sulfate. The solvent was completely distilled off under reduced pressure at below 50° C. to get the title compound as a residue.
- Aqueous hydrochloric acid solution 7.5 ml
- the aqueous layer was extracted with cyclohexane.
- the solvent was completely distilled off from the reaction mixture.
- the obtained crude compound was purified by column chromatography using a mixture of cyclohexane and ethyl acetate to get the title compound as a semi-solid.
- N—N-diisopropylacetamide (70 grams) added to a solution of 3500 ml of 1 molar LiHMDS solution, 650 ml of tetrahydrofuran at ⁇ 50 to ⁇ 70° C. Stirred the reaction mixture for 25 minutes at ⁇ 70 to ⁇ 75° C. Added 185 gram of ethyl-4-chloro-3-hydroxy butanoate at ⁇ 73 to ⁇ 75° C. Stirred the reaction for 1 hour at ⁇ 48 to ⁇ 45° C. Quenched the reaction mixture with chilled water followed by hydrochloric acid solution. Separated the organic and inorganic phases. Washed the organic layer with 10% sodium bicarbonate solution. Dried the organic layer using sodium sulfate and distilled the solvent completely under reduced pressure. Purified the residue in petroleum ether to get the title compound of formula-12.
- the dihydroxy compound of formula-4x (1 gram) was dissolved in 5 ml of ethylene glycol at 25-30° C.
- Aqueous sodium hydroxide solution (05 gram in 2 ml) was added to the above reaction mixture at 25-30° C.
- the reaction mixture was heated to 90-95° C.
- the reaction mixture was stirred at 90-95° C. for 4 hours.
- the reaction mixture was cooled to 25-30° C.
- Water (5 ml) was added to the above reaction mixture at 25-30° C. Quenched the reaction mixture with aqueous hydrochloric acid.
- Ethyl acetate (20 ml) was added to the reaction mixture and stirred for 10 minutes at 25-30° C. The ethyl acetate layer was separated.
- the pH of the reaction mixture was adjusted to 9.2 with aqueous sodium hydroxide solution.
- the solvent completely distilled off under reduced pressure at below 50° C.
- the reaction mixture was filtered through hyflow and washed with water.
- Calcium chloride solution was added to the reaction mixture was slowly at 25-35° C. Stirred the reaction mixture was 60 minutes at 35-45° C. The solid was filtered and washed with water.
- IR spectrum 3380, 2967, 1601, 1547, 1509, 1437, 1334, 1382, 1228, 1153, 843, 775 cm ⁇ 1 .
- a solution of 15 grams of tertiary butylamine salt compound of formula-5a and 75 ml of water is cooled to 25-30° C.
- D (v, 0.1) is 4.9 ⁇ m; D (v, 0.5) is 45.86 ⁇ m; D (v, 0.9) is 180.59 ⁇ m.
- D (v, 0.1) is 2.46 ⁇ m; D (v, 0.5) is 12.85 ⁇ m; D (v, 0.9) is 46.43 ⁇ m.
- a solution of 15 grams of tertiary butylamine salt compound of formula-5a and 75 ml of water is cooled to 25-30° C.
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Abstract
Description
Wherein denotes a single or a double bond and R is a hydrophobic anchor or a residue of HMG CoA reductase inhibitor selected from any one of the compound of formula-a to formula-g,
wherein denotes a single or a double bond and M is H, Na+, K+, Mg+2, Ca+2 and R is as defined above.
wherein denotes a single or a double bond and M is H, Na+, K+, Mg+2, Ca+2 and R is defined as above.
which comprises of the following steps:
-
- a) reacting the sulfone compound of general formula-2 with an amide compound of general formula-3 in presence of a suitable base in a suitable solvent to provide an olefin compound of general formula-4,
- b) deprotecting the alcohol or diol protecting group of olefin compound of general formula-4 by acid hydrolysis using suitable acid in a suitable solvent to provide dihydroxy compound of general formula-4x,
- c) reacting the dihyroxy compound of general formula-4x with a suitable base like alkali and/or alkaline metal hydroxide to provide alkali metal salt of corresponding acid compound of formula-4x followed by treating with suitable organic amine to provide corresponding organic amine salt compound of general formula-5,
- d) treating the organic amine salt compound of general formula-5 with a suitable acid to provide free acid compound of general formula-6,
- e) the alkenyl double bond in free acid compound of general formula-6 may be reduced by hydrogenation (H2/Pd/C) to provide saturated alkyl acid compound of general formula-7,
- f) converting the dihydroxy compound of general formula-4x or free acid compound of general formula-6 or its organic amine compound of general formula-5 or alkyl acid compound of formula-7 into their pharmaceutically acceptable salt compounds of the general formula-1 by treating with a suitable alkali base followed by treating with alkali or alkaline earth metal salts in a suitable solvent.
-
- a) reacting diphenyl phosphine oxide compound of general formula-8 with an amide compound of general formula-3 in presence of suitable base in a suitable solvent to provide olefin compound of general formula-4,
- b) converting the olefin compound of general formula-4 into statins or their pharmaceutically acceptable salts of general formula-1 as per the process disclosed in first aspect of the present invention.
-
- a) reacting the triphenyl phosphonium bromide compound of general formula-9 with an amide compound of general formula-3 in presence of a suitable base in a suitable solvent to provide olefin compound of general formula-4,
- b) converting the olefin compound of general formula-4 into statins or their pharmaceutically acceptable salts of general formula-1 as per the process disclosed in first aspect of the invention.
-
- Wherein
- P1 and P2 are alcohol protecting group or
- P1 and P2, taken together to form a 1,3-diol protecting group,
- R′ & R″ is independently selected from hydrogen, lower alkyl, alkyl, aryl or aralkyl or
- R′ & R″ taken together with the linking nitrogen atom form a mono or bicyclic heterocycle which may optionally contain in all ring moieties further nitrogen, oxygen or sulphur heteroatoms and which may optionally be substituted.
-
- a) reacting chloro hydroxy compound of formula-10 with an amide compound of general formula-11 in a suitable solvent to provide chloro hydroxy amide compound of general formula-12,
- b) reducing the chloro hydroxy amide compound of formula-12 selectively with a suitable reducing agent in a suitable solvent to provide dihydroxy compound of general formula-13,
- c) protecting the dihydroxy compound of general formula-13 by treating with a suitable alcohol or diol protecting agent in a suitable solvent to provide the protected dihydroxy compound of general formula-14,
- d) reacting the protected dihydroxy compound of general formula-14 with suitable acetate salt in presence of a phase transfer catalyst in a suitable solvent to provide the compound of general formula-15,
- e) hydrolyzing the compound of general formula-15 in presence of a suitable base in a suitable solvent to provide hydroxy amide compound of general formula-16,
- f) oxidizing the hydroxy amide compound of general formula-16 with a suitable oxidizing agent in presence of a catalyst in a suitable solvent to provide the amide compound of general formula-3.
-
- a) reacting the ester compound of formula-17 with an amine compound of general formula-19 with or without presence of solvent to provide the corresponding dihydroxy compound of general formula-20,
- b) optionally treating the ester compound of formula-17 with suitable acid in a suitable chloro solvent to provide lactone compound of formula-18 followed by reacting with an amine compound of general formula-19 to provide the corresponding dihydroxy compound of general formula-20,
- c) protecting the corresponding dihydroxy compound of general formula-20 by treating with a suitable alcohol or diol protecting agent in a suitable solvent to provide the protected dihydroxy compound of general formula-16,
- d) oxidizing the dihydroxy amide compound of general formula-16 with a suitable oxidizing agent in presence of a catalyst in a suitable solvent to provide the amide compound of general formula-3.
-
- a) reacting the compound of general formula-21 with thiol compound of general formula-22 in presence of a suitable base with or without presence of a suitable solvent to provide a novel sulfide compound of general formula-23,
- b) oxidizing the sulfide compound of general formula-23 with an oxidizing agent in presence of an appropriate catalyst in a suitable solvent, to provide a novel sulfone compound of general formula-2 and sulfoxide compound of general formula-24 can be prepared by controlled oxidation of sulfide.
wherein denotes a single or a double bond and M is H, Na+, K+, Mg+2, Ca+2 and R is as defined above,
which comprises of reacting a sulfone compound of general formula-2,
-
- Wherein
- P1 and P2 are alcohol protecting group or
- P1 and P2, taken together to form a 1,3-diol protecting group,
- R′ & R″ is independently selected from hydrogen, lower alkyl, alkyl, aryl or aralkyl or
- R′ & R″ taken together with the linking nitrogen atom form a mono or bicyclic heterocycle which may optionally contain in all ring moieties further nitrogen, oxygen or sulphur heteroatoms and which may optionally be substituted.
in presence of a suitable base selected from alkali or alkaline earth metal alkoxides/hydroxides, alkali metal carbonates, amide bases, alkyl metals and metal hydrides preferably alkali metal carbonates in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ketone solvents, ester solvents or mixtures thereof preferably polar aprotic solvents, followed by isolation using suitable hydrocarbon solvents to provide olefin compound of general formula-4,
wherein M is H, Na+, K+, Mg+2, Ca+2 and R is as defined above
which comprises of reacting the diphenyl phosphine oxide compound of general formula-8,
Wherein R is defined as above which is linked to phosphorus atom with a methylene group (—CH2—)
With an amide compound of general formula-3
wherein P1, P2, R′ & R″ are defined as above
in presence of a suitable base selected from alkali or alkaline earth metal alkoxide/hydroxide, alkali metal carbonates, amide bases, alkyl metals and metal hydrides preferably amide bases in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ketone solvents, ester solvents or mixtures thereof preferably polar aprotic solvents, followed by isolation using suitable hydrocarbon solvents to provide olefin compound of general formula-4,
Wherein R is defined as above which is linked to phosphorus atom with a methylene group (—CH2—)
With an amide compound of general formula-3,
wherein P1, P2, R′ & R″ are defined as above
in presence of a suitable base selected from alkali or alkaline earth metal alkoxide/hydroxide, alkali metal carbonates, amide bases, alkyl metals and metal hydrides preferably alkali metal carbonates in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ketone solvents, ester solvents or mixtures thereof preferably polar aprotic solvents, followed by isolation using suitable hydrocarbon solvents to provide olefin compound of general formula-4,
-
- Wherein
- P1 and P2 are alcohol protecting group or
- P1 and P2, taken together to form a 1,3-diol protecting group,
- R′ & R″ is independently selected from hydrogen, lower alkyl, alkyl, aryl or aralkyl or
- R′ & R″ taken together with the linking nitrogen atom form a mono or bicyclic heterocycle which may optionally contain in all ring moieties further nitrogen, oxygen or sulphur heteroatoms and which may optionally be substituted.
Preferably the 1,3-diol protecting group selected from the following
-
- Wherein R5 and R6 are independently selected from C1-C10 alkyl,
- Or R5 and R6, taken together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or cycloheptyl ring; and Z is an oxo or thio group
- a) reacting the chloro hydroxy compound of formula-10
-
- with an amide compound of general formula-11
-
- in a suitable solvent selected from hydrocarbon solvents or polar aprotic solvents preferably polar aprotic solvents to provide the chloro hydroxy amide compound of general formula-12,
- b) reducing the chloro hydroxy amide compound of general formula-12 selectively with a suitable reducing agent like sodiumborohydride, zinc borohydride and lithiumborohydride preferably sodiumborohydride along with borane reagent like alkyl borane, dialkyl alkoxy borane preferably dialkyl alkoxy borane like diethyl methoxy borane in a suitable polar aprotic solvent like tetrahydrofuran to provide the dihydroxy compound of general formula-13,
- c) protecting the dihydroxy compound of general formula-13 by treating it with a suitable alcohol or diol protecting agent in a suitable hydrocarbon solvents or ketone solvent preferably ketone solvent like acetone to provide protected dihydroxy compound of general formula-14,
- d) reacting the protected dihydroxy compound of general formula-14 with an acetate salt like sodium acetate in presence of a suitable phase transfer catalyst in a suitable solvent selected from ketone solvent like acetone to provide the compound of general formula-15,
- e) hydrolyzing the compound of general formula-15 in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, butanol preferably methanol and in presence of an alkali metal carbonate like sodium carbonate or potassium carbonate preferably potassium carbonate to provide the compound of general formula-16,
- f) oxidizing the compound of general formula-16 with a suitable oxidizing agent like sodium hypochlorite and in presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) in a suitable solvent like acetone or in presence of oxalyl chloride and dimethyl sulfoxide to provide the amide compound of general formula-3.
-
- a) reacting the ester compound of formula-17,
-
-
- with an amine compound of general formula-19,
-
-
-
- R′ & R″ are defined as above
- with or without the presence of a solvent to give dihydroxy amide compound of general formula-20,
-
-
- b) optionally treating the ester compound of formula-17 with suitable acid like trifluoroacetic acid to get the lactone compound of formula-18 followed by reacting with amine compound of general formula-19 with or without a solvent to provide the dihydroxy amide compound of general formula-20,
-
- c) protecting the dihydroxy amide compound of formula-20 by treating with alcohol or diol protecting agent in a suitable solvent selected from ketone solvent, ester solvent, chloro solvent and hydrocarbon solvents preferably ketone solvent to provide protected dihydroxy compound of formula-16,
-
- d) oxidizing the compound of formula-16 with a suitable oxidizing agent like sodium hypochlorite in presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) in a suitable solvent like acetone or in presence of oxalyl chloride/dimethyl sulfoxide in a suitable solvent like chloro solvents to provide the amide compound of general formula-3.
Wherein R is defined as above which is linked to the sulphur atom with a methylene group (—CH2—) and R1 is defined as above,
which comprises of the following steps:
-
- a) treating the compound of general formula-21
R-L Formula-21- Wherein L is a leaving group such as halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, preferably halogen, more preferably bromo and R is defined as above which is linked to the leaving group with a methylene group (—CH2—);
- with a thiol compound of general formula-22
R1SH Formula-22 - wherein R1 is defined as above
- in presence of a suitable base like sodium hydroxide with or without presence of a suitable solvent selected from chloro solvents, ketone solvents, ester solvents, polar protic solvents or mixtures thereof, preferably keto solvents, more preferably acetone to provide a novel sulfide compound of general formula-23,
- a) treating the compound of general formula-21
-
-
- wherein R is defined as above which is linked to the sulphur atom with a methylene group (—CH2—) and R1 is defined as above
- b) oxidizing a sulfide compound of general formula-23 with an oxidizing agent like metachloro per benzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, preferably hydrogen peroxide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents, chloro solvents or mixture thereof, preferably chloro solvents, more preferably methylene chloride to provide the novel sulfone compound of general formula-2 and a novel sulfoxide compound of general formula-24 can be prepared by controlled oxidation of sulfide.
-
in presence of a suitable alkali metal carbonate like potassium carbonate in a polar aprotic solvent like dimethyl sulfoxide, followed by isolation using cyclohexane to provide corresponding olefin compound of formula-4a′,
in presence of a suitable base like potassium carbonate in a polar aprotic solvent like dimethyl sulfoxide to provide olefin compound of formula-4a,
in presence of an amide base like sodium bis(trimethylsilyl)amide (NaHMDS) in polar aprotic solvent like tetrahydrofuran to provide olefin compound of formula-4a,
in presence of a suitable base like potassium carbonate in a polar aprotic solvent like dimethyl sulfoxide to provide corresponding olefin compound of or formula-4a′,
in presence of an alkali metal carbonates like potassium carbonate in a suitable polar aprotic solvent like dimethyl sulfoxide to provide olefin compound of formula-4a,
-
- a) placing rosuvastatin calcium in a clear polyethylene bag tied with a thread,
- b) placing the primary packing containing rosuvastatin calcium inside a black colour polyethylene bag and sealing it,
- c) placing the above double polyethylene bag inside a triple laminated bag,
- d) placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container
-
- a) placing rosuvastatin calcium in a clear polyethylene bag tied with a thread,
- b) placing the primary packing containing rosuvastatin calcium inside a black colour polyethylene bag and sealing it,
- c) placing the above double polyethylene bag inside a triple laminated bag,
- d) placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container.
Claims (2)
Applications Claiming Priority (3)
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IN1864/CHE/2006 | 2006-10-09 | ||
IN1864CH2006 | 2006-10-09 | ||
PCT/IN2007/000459 WO2008044243A2 (en) | 2006-10-09 | 2007-10-05 | Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof |
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US20100056783A1 US20100056783A1 (en) | 2010-03-04 |
US8404841B2 true US8404841B2 (en) | 2013-03-26 |
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US12/531,386 Expired - Fee Related US8404841B2 (en) | 2006-10-09 | 2007-10-05 | Process for the preparation of statins and their pharmaceutically acceptable salts thereof |
Country Status (6)
Country | Link |
---|---|
US (1) | US8404841B2 (en) |
EP (1) | EP2086945B1 (en) |
ES (1) | ES2567171T3 (en) |
HU (1) | HUE028475T2 (en) |
SI (1) | SI2086945T1 (en) |
WO (1) | WO2008044243A2 (en) |
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US8987444B2 (en) | 2010-01-18 | 2015-03-24 | Msn Laboratories Private Limited | Process for the preparation of amide intermediates and their use thereof |
US9133132B2 (en) | 2010-11-29 | 2015-09-15 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Method for the preparation of high-purity pharmaceutical intermediates |
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WO2008044243A9 (en) | 2008-11-13 |
SI2086945T1 (en) | 2016-05-31 |
EP2086945B1 (en) | 2016-01-06 |
HUE028475T2 (en) | 2016-12-28 |
WO2008044243A3 (en) | 2010-02-11 |
EP2086945A2 (en) | 2009-08-12 |
EP2086945A4 (en) | 2010-12-29 |
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US20100056783A1 (en) | 2010-03-04 |
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